title: Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways.
abstract: Angiotensin (Ang) II plays a vital role in vascular smooth muscle cell (VSMC) growth and proliferation. Angiotensin-converting enzyme 2 (ACE2) is a specific Ang II-degrading enzyme but its role in VSMC proliferation remains largely unknown. We hypothesized that ACE2 might suppress Ang II-mediated oxidative stress and VSMC proliferation. Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with Ang II (100nM) for 6h and 24h, respectively. Exposure to Ang II resulted in significant increases in suppressor of cytokine signaling 3 (SOCS3) expression and phosphorylation levels of JAK2, STAT3 and ERK1/2 linked with elevated superoxide production and cell proliferation in HUASMCs. These changes were strikingly prevented by administration of ERK1/2 inhibitor PD98059 (10μM) and JAK/STAT inhibitor WP1066 (5 μM) but were largely aggravated by ACE2 inhibitor DX600 (0.5 μM). More importantly, treatment with human recombinant ACE2 (hrACE2; 1mg/ml) dramatically prevented Ang II-mediated SOCS3 expression and the JAK2-STAT3 and ERK1/2 signaling, and resulted in attenuation of superoxide production and cell proliferation in HUASMCs. Intriguingly, downregulation of profilin-1 with profilin-1 siRNA (50 nM) was able to abolish Ang II-induced upregulations of profilin-1 expression, ERK1/2 phosphorylation and superoxide production with attenuation of VSMC proliferation. In conclusion, treatment with hrACE2 prevents Ang II-mediated activation of the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways, contributing to attenuation of superoxide generation and cell proliferation in HUASMCs, suggesting a protective mechanism of ACE2 against Ang II-mediated oxidative stress and VSMC proliferation. ACE2 may represent a potential candidate to prevent and treat vascular disorders.
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory of Vascular Biology, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Song
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jin
authors.forename: Xi
authors.initials: X
authors.lastname: Yu
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Zhang
authors.forename: Huimin
authors.initials: H
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.forename: Yingle
authors.initials: Y
authors.lastname: Xu
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Ye
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology; D000085962:Angiotensin-Converting Enzyme 2; D049109:Cell Proliferation; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051304:Profilins / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology
chemical_list: C495738:PFN1 protein, human; D051304:Profilins; D044140:Receptor, Angiotensin, Type 1; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000804:Angiotensin II; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2
keywords: Angiotensin II; Angiotensin-converting enzyme 2; Cell proliferation; Oxidative stress; Profilin-1; Suppressor of cytokine signaling 3